Wolfram syndrome: hereditary diabetes mellitus with brainstem and optic atrophy.

Wolfram syndrome was originally described as a combination of familial juvenile-onset diabetes mellitus and optic atrophy. Other neurological features subsequently emerged, and "DIDMOAD" (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) became a commonly accepted acronym. Here, we describe 4 further cases from 2 families, in whom there occurred previously unrecognized neurological features, central apnea and neurogenic upper airway collapse, together precipitating primary respiratory failure (fatal in 1 case), startle myoclonus (in 2 unrelated cases), axial rigidity, and Parinaud's syndrome. Magnetic resonance images revealed striking brainstem atrophy affecting, in particular, the pons and midbrain. The mitochondrial DNA from 3 cases (and relatives) showed no evidence of any of the previously reported abnormalities. These neurological and neuroradiological features, in conjunction with (1) analyses showing the neurodegenerative origin of optic atrophy, deafness, diabetes insipidus, and incontinence, (2) other previously reported neurological complications (including anosmia, ataxia, epilepsy, and neuropsychiatric and cognitive abnormalities), and (3) the very small number of published postmortem studies, indicate that Wolfram syndrome should be reemphasized as a unique hereditary neurodegenerative disorder with prominent optic atrophy and diabetes mellitus.

The T-cell receptor beta locus and susceptibility to multiple sclerosis.

Assessments of genetically determined variations in the T-cell antigen receptor in multiple sclerosis (MS) have yielded conflicting results. We used three restriction fragment length polymorphisms (RFLPs) and a polymorphic microsatellite repeat as markers for the T-cell receptor (TCR) beta locus (7q32-35) in multiplex MS families. Affected sibling-pair analysis of the RFLP data failed to show evidence for linkage (127 families) whereas analysis of the microsatellite data (86 families) provided weak evidence for linkage with a maximum lod score of 0.98 (p < 0.05). We repeated the analysis in those families (n = 53) in which the affected sibling pairs were concordant for the HLA haplotype DR15/DQ6. This altered the proportion of affected siblings sharing 0, 1, 2 RFLP haplotypes from 0.24, 0.50, and 0.26 (p = NS) before stratification to 0.16, 0.41, and 0.43 (p < 0.05) in the DR15/DQ6 positive pairs alone; for the microsatellite data, sharing altered from 0.16, 0.50, and 0.34 (p < 0.05) in all pairs to 0.07, 0.49, and 0.44 (p < 0.01) in the DR15/DQ6 concordant siblings.

Susceptibility to multiple sclerosis and the immunoglobulin heavy chain variable region.

A haplotype marker consisting of three biallelic restriction fragment length polymorphism (RFLP) loci from the VH-2 variable gene family was examined in 124 families with sibling pairs concordant for multiple sclerosis, 178 unrelated patients and 159 unaffected controls to investigate the role of the immunoglobulin heavy chain gene cluster in susceptibility to multiple sclerosis. Evidence for linkage was assessed using the affected sibling pair method of identity by descent, modified to allow for haplotype sharing on a probabilistic basis in families where haplotypes could not be assigned with certainty. The estimated probabilities of affected siblings sharing 0, 1 or 2 haplotypes were Z0 = 0.20, Z1 = 0.45, Z2 = 0.35. This deviation from the expected sharing probabilities of Z0 = 0.25, Z1 = 0.5, Z2 = 0.25 provides evidence for weak linkage (P < 0.05; equivalent to a lod score of 0.84); however, no significant allelic or haplotypic association was observed. Linkage without a population association suggests that a gene encoded on 14q confers susceptibility to multiple sclerosis, although this is not any of the existing VH-2 polymorphisms.

Multiple sclerosis and the HLA-D region: linkage and association studies.

Inheritance patterns of multiple sclerosis (MS) in multiplex families suggest a complex aetiology involving environmental and genetically determined components. The association between the HLA class II DR15, DQ6, Dw2 haplotype and MS has been well documented in patients with ancestral origins in Northern Europe. Conversely, linkage analysis of this region in multiplex families, derived from a population base, has generated negative results. Thus, given the Dw2 specificity association, evidence implicating this locus in disease susceptibility appears contradictory. We have collected and determined the HLA-DR and -DQ haplotypes of 115 sibling pairs with multiple sclerosis, and confirm a significant association with the Dw2-associated haplotype, both in index cases and their affected siblings compared with controls. However, using a sibling pair linkage analysis that restricts haplotype sharing probabilities to defined genetic models, we have not observed linkage of this region to susceptibility in MS. We discuss the basis for association and linkage and conclude that the DR15, DQ6, Dw2 haplotype does represent a susceptibility locus but its contribution to the pathogenesis is small; although it may interact epistatically with other susceptibility genes, this haplotype is not necessary for disease expression.

No linkage between multiple sclerosis and the T cell receptor alpha chain locus.

Susceptibility to multiple sclerosis (MS) is genetically determined but it is thought that more than one gene contributes to development of the disease. We report a study of linkage to one candidate, the T cell receptor alpha chain locus, on chromosome 14, in affected sibling pairs. Markers with high polymorphism information contents were used to assign haplotypes identical by descent and state. Forty nine pairs were studied using restriction fragment length polymorphisms (RFLP) and 82 pairs were investigated using a microsatellite repeat polymorphism. In neither case did genotype or haplotype sharing differ significantly from expected rates. Stratification of patients according to DR15 status did not alter the distribution of haplotypes in affected siblings. We conclude that the T cell receptor alpha locus is not linked to susceptibility in patients with MS from the United Kingdom.

Levamisole: as adjuvant to cyclic chemotherapy in breast cancer.

The addition of levamisole, administered in adjunctive manner between the cycles of conventional high dose chemotherapy in patients with hormone resistant end state breast cancer substantially improved the survival of treated patients. Analysis of this double-blind study in 60 such patients suggests that improvement in remission status and survival is related to better tolerability of such cytotoxic therapy as regards both specific and nonspecific cytotoxicity. This improved tolerability enabled patients to receive higher doses of cytotoxic drugs over a shorter time period resulting in an improved remission rate and ultimate survival.